The signals required to maintain antibody-secreting plasma cell pools and serum antibody titers remain poorly defined. This proposal is focused on definitively determining whether persisting antigen plays a key role in maintaining serum antibody titers. The proposition that maintenance of antigen-specific serum titers requires persistence of antigen would have profound implications for vaccine design as all immunizing antigens would have to be engineered to form a lifelong depot in the body. To eliminate the seeding of the BM PC pool by antigen-stimulated B cell feeder populations, B cells will be deprived of T cell help and the B cell receptor of the memory B cell population will be experimentally revised so as to not be responsive to antigen. If it is found that the BM PC pool needs to be maintained by feeder populations it will be a demonstration of the need for persistent antigen for the maintenance of protective antibody titers. Overall, the experiments within this proposal will serve to better define the requirements for serum antibody maintenance and may suggest new ways to optimize these titers, thereby fulfilling the mission of the Transfusion Medicine and Cellular Therapeutics Program of the NHLBI. PUBLIC HEALTH RELEVANCE: The proposed studies will test whether antigen persistence plays a role in maintaining plasma cell populations and therefore antibody titers. This will inform us about ways to optimize vaccine antigen design. It will also increase our understanding about the regulation of a cell subset that is responsible for the production of antibodies that both mediate autoimmune disease (such as rheumatoid arthritis) and protect our bodies from infection.